Microsatellite Stability Status in Oncology: MSS/MSI-H as a Diagnostic, Prognostic, and Therapeutic Biomarker in the Era of Personalized Oncology

Abstract

Microsatellite instability (MSI) is a major phenotype of genomic instability in cancer and is predominantly associated
with deficiency of the DNA mismatch repair (MMR) system. Loss of MMR function causes accumulation of replication errors,
particularly within microsatellite regions, producing the MSI-high (MSI-H) phenotype and often a hypermutated, highly
neoantigenic tumour state. In contemporary oncology, MSI-H/dMMR has diagnostic, hereditary cancer-screening, prognostic
and predictive implications. Immune checkpoint inhibitors have transformed MSI-H/dMMR into one of the first clinically
successful tissue-agnostic biomarkers. Nevertheless, MSI-H is not an absolute predictor of immunotherapy benefit, and
microsatellite-stable (MSS) cancers are themselves biologically heterogeneous. This review discusses the molecular basis and
diagnostic assessment of MSI/MMR, Lynch syndrome, prognostic significance, checkpoint inhibition, mechanisms of resistance,
liquid biopsy. We further propose an integrated “MSI-plus” framework in which MSI/MMR status is treated as the entry point
to multidimensional genomic, immune and dynamic profiling rather than as a stand-alone binary biomarker.